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在嗜睡症小鼠模型中,睡眠-觉醒动态、猝倒和 EEG 快德尔塔功率的性别相关差异。

Sex-related differences within sleep-wake dynamics, cataplexy, and EEG fast-delta power in a narcolepsy mouse model.

机构信息

Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

出版信息

Sleep. 2022 Jul 11;45(7). doi: 10.1093/sleep/zsac058.

Abstract

Narcolepsy type 1 (NT1) is a sleep-wake disorder caused by selective loss of hypocretin (HCRT, also called orexin) neurons. Although the prevalence of NT1 is equal in men and women, sex differences in NT1 symptomatology have been reported in humans and other species. Yet, most preclinical studies fail to include females, resulting in gender bias within translational drug development. We used hcrt-tTA;TetO DTA mice (NT1 mice) that lose their HCRT neurons upon dietary doxycycline removal to examine in detail the effect of sex on NT1 symptoms and sleep-wake characteristics. We recorded 24-h electroencephalography (EEG), electromyography (EMG), and video in adult male and female NT1 mice for behavioral state quantification. While conducting this study, we recognized another type of behavioral arrest different from cataplexy: shorter lasting and with high δ power. We termed these delta attacks and propose a set of criteria for quantifying these in future research. Our findings show that both sexes exhibit high behavioral state instability, which was markedly higher in females with more behavioral arrests interrupting the wake episodes. Females exhibited increased wake at the expense of sleep during the dark phase, and decreased rapid eye movement (REM) sleep during the 24-h day. During the dark phase, fast-δ (2.5-4 Hz) in non-rapid eye movement (NREM) sleep and θ (6-10 Hz) EEG spectral power in REM sleep were lower in females compared to males. We demonstrate that biologically driven sex-related differences exist in the symptomatology of NT1 mice which calls for including both sexes in future research.

摘要

发作性睡病 1 型(NT1)是一种由下丘脑泌素(HCRT,也称为食欲素)神经元选择性缺失引起的睡眠-觉醒障碍。尽管 NT1 在男性和女性中的患病率相等,但在人类和其他物种中已报道 NT1 症状存在性别差异。然而,大多数临床前研究未能纳入女性,导致药物转化开发中存在性别偏见。我们使用 hcrt-tTA;TetO DTA 小鼠(NT1 小鼠),当饮食中去除强力霉素时会失去其 HCRT 神经元,以详细研究性别对 NT1 症状和睡眠-觉醒特征的影响。我们记录了成年雄性和雌性 NT1 小鼠 24 小时的脑电图(EEG)、肌电图(EMG)和视频,以进行行为状态量化。在进行这项研究时,我们发现了另一种与猝倒不同的行为性发作:持续时间更短,δ 功率更高。我们将这些称为δ发作,并提出了一套在未来研究中量化这些发作的标准。我们的研究结果表明,两性都表现出高行为状态不稳定,而雌性的行为发作中断觉醒期更为明显。与雄性相比,雌性在夜间表现出更多的觉醒,而睡眠减少,并且在 24 小时周期内快速眼动(REM)睡眠减少。在夜间,非快速眼动(NREM)睡眠中的快 δ(2.5-4 Hz)和 REM 睡眠中的 θ(6-10 Hz)EEG 频谱功率在雌性中低于雄性。我们证明,NT1 小鼠的症状存在生物学驱动的性别相关差异,这呼吁在未来的研究中纳入两性。

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